Objective. To evaluate the clinical characteristics, response to treatment and outcome of Zollinger-Ellison syndrome (ZES)-like gastric acid hypersecretors. Methods. Over a 20-year period, patients with gastric acid hypersecretion in the absence of ZES were enrolled in an open label prospective trial evaluating the efficacy of lansoprazole. Following baseline evaluations, patients were treated with escalating doses of lansoprazole based on the results of gastric acid analysis. Following stabilization, patients were followed on a 6 monthly basis with interval history, physical examination, endoscopy with gastric biopsies, gastric acid analysis, and laboratory studies. Results. The study group represented 21 patients (median age 47 years, 86% male, 91% Caucasian). Historically, complicated ulcer disease was frequent and symptoms had been present for a median of 10 years before study entry. All patients responded to lansoprazole (median dose 90 mg/day) with excellent control of gastric acid hypersecretion. Mucosal relapse was infrequent and no major complications developed while on therapy. Conclusions. ZES-like gastric acid hypersecretion presents similarly to the classic syndrome. Lansoprazole titrated to gastric acid output is effective in healing mucosal disease and preventing relapse. © 2011 Informa Healthcare.